The Neurotoxin Institute (NTI) is a multidisciplinary organization created to serve as a comprehensive independent source of information related to the basic science and the clinical applications of neurotoxins. The Institute fosters the learning and teaching of both theory and practical techniques, and encourages further research in support of these goals.

NEW Online CME Activity

Neurotoxins may be synthetic or endogenous compounds derived from species as diverse as bacteria, fungi, spiders, marine life, and man. Seven botulinum neurotoxin (BoNT) serotypes (A, B, C, D, E, F, and G), which are produced by Clostridium botulinum and other Clostridium species, inhibit neurotransmitter release from nerve terminals. These serotypes of BoNT are antigenically dissimilar, utilize distinct but related mechanisms of action, and are not interchangeable. Only BoNT serotypes A and B are approved by the Food and Drug Administration for treatment of neurological disorders and for cosmetic indications.

Neuroexocytosis, a multistage process leading to the fusion of synaptic vesicles with the plasma membrane, involves proteins collectively called SNAREs (soluble N-ethylmaleimide–sensitive factor [NSF] attachment protein receptors). Following calcium entry into the....[more]

Dystonia is defined as a neurological syndrome characterized by involuntary, sustained, patterned, and often repetitive muscle contractions of opposing muscles, resulting in twisting or squeezing movements, abnormal postures, or both. Dystonia can be subdivided according to anatomical distribution into focal, segmental, and generalized. Although pathogenesis-targeted therapy is not yet available, treatment strategies designed to relieve motor symptoms and pain have markedly improved the quality of life of patients with dystonia. Local chemodenervation with botulinum neurotoxin (BoNT) is considered the treatment of choice for patients with focal dystonia, whereas medications and deep brain stimulation are usually used in patients with segmental and generalized dystonia.

The hyperkinetic motor disorders are a heterogeneous group of conditions characterized by abnormal, excessive, involuntary movements. Although for many of these disorders the precise etiology and pathogenesis remain undefined, hemifacial spasm (HFS) and painful legs and moving toes syndrome (PLMTS) are well-described hyperkinetic motor disorders known to be associated with peripheral nerve damage. HFS typically presents with involuntary, unpredictable contractions of muscles innervated by the facial nerve. The most common cause of HFS is extrinsic compression of the ipsilateral facial nerve in the posterior fossa, usually by an anomalous or ectatic intracranial blood vessel. Involuntary movements in PLMTS involve the toes, occurring in association with pain or paresthesias; while the exact pathologic mechanism is unknown, electromyography usually reveals patterns suggestive of peripheral neuropathy or radiculopathy. The most effective treatment options for HFS are surgery or chemodenervation with botulinum toxin. Management of PLMTS is focused predominantly on pain management; satisfactory responses to chemodenervation are uncommon. This section will review the characteristic findings of HFS and PLMTS, and discuss approaches to diagnosis and treatment.

Hyperkinetic movement disorders may arise as isolated phenomena or be manifestations of a systemic disorder. The disorders discussed in this section present with diverse clinical findings, and vary in incidence from relatively common to extremely rare. There is only limited information available regarding the specific mechanisms underlying their development. This section will briefly describe the pertinent features of essential tremor, palatal tremor, tics, stiff-person syndrome, myoclonus, and isolated muscle spasm. An organized, methodical search for characteristic features of these disorders will facilitate an accurate clinical diagnosis and support identification of an appropriate treatment option. For some of these conditions, injection of botulinum toxin into involved muscles may be considered as an effective adjunct to standard medical therapies.

Blepharospasm and Strabisimus

Abstract

Benign Essential Blepharospasm (BEB) is a disabling focal dystonia marked by involuntary blinking or sustained eyelid closure. It may be caused by spasms of the orbicularis oculi muscle or failure of the superior levator palpebrae muscle to contract. Blepharospasm has a substantial impact on quality of life and may lead to depression and anxiety. No medical or surgical treatments for blepharospasm were effective before the introduction of botulinum neurotoxin A (BoNT-A). Currently, two BoNT-A formulations are approved by the FDA for the management of BEB, and BoNT-A is considered standard of care. BoNT-A provides high response rates and improves patient quality of life with minor adverse events, including ptosis, epiphora, keratitis, dry eyes, and diplopia. Other BoNT formulations are being studied as well. Strabismus, misalignment of the eyes, is a disabling condition that frequently affects pediatric populations but can also affect adults. With a range of presentations, the treatments for strabismus vary and include corrective lenses, eye exercises, occlusive therapy, and surgery. BoNT-A is frequently used as an adjunct and alternative to strabismus surgery. BoNT-A therapy improves vision in more than 50% of patients for 6 months or longer after injection. Optimal strategies for dosing and injecting BoNT are discussed.

Cerebral palsy (CP) is the most common cause of chronic neurological impairment in children. CP denotes a spectrum of neurological disorders arising from a lesion to brain areas involved in the initiation of movement, and clinical manifestation vary with the severity of the underlying insult. It is a syndrome of diverse etiologies and many potential risk factors, and the brain insult may occur pre-, peri-, or postnatally. While the fundamental motor impairment is reflected in abnormalities of muscle tone, which may range from minimal spasticity to devastating quadriplegia, many patient with CP will have additional findings, including epilepsy, mental retardation, speech and visual disturbance, gastrointestinal and feeding disorders, chronic pain, and others. Comprehensive management of motor disorders in CP is directed toward improvement of spasticity, dystonia, muscle stiffness, contractures and joint deformities, and other manifestations of poor motor control, such as sialorrhea. Treatment requires multidisciplinary care, adaptive devices, and symptomatic and supportive therapies. Pharmacologic management may warrant the use of combinations of medications with different mechanisms of action. Chemodenervating agents (phenol, alcohol, and botulinum neurtoxin) and specialized orthopedic surgical procedures have become established treatment options to improve focal spasticity, dystonia, and other manifestations associated with CP. This educational activity will review pertinent information relevant to the etiology, epidemiology, clinical manifestations and management of CP, with emphasis on contemporary usage of botulinum neurotoxin.

Upper motor neuron syndrome (UMNS) is a collective term for positive signs (ie, different clinical forms of involuntary muscle overactivity) and negative signs (impaired voluntary movement and motor control) that occur in patients with lesions of the descending corticospinal system. Such lesions may occur in patients with cerebral palsy or multiple sclerosis and in those who have experienced stroke, traumatic brain injury, or spinal cord injury. Patients with UMNS may experience impaired voluntary and involuntary motor activity and interference with limb positioning, along with poor hygiene, pain, abnormal gait, and reduced activities of daily living. Effective treatment often requires integration of a variety of conservative, interventional, and surgical options that are targeted to a specific patient’s functional impairment. Botulinum neurotoxin (BoNT), a recent addition to the treatment armamentarium, has been shown to reduce upper and lower limb spasticity and other forms of muscle overactivity in the UMNS. In 2010, the indication for BOTOX® (onabotulinumtoxinA [BoNT-A]) was expanded by the US Food and Drug Administration (FDA) to include treatment of upper limb spasticity in adults .

Hyperhydrosis is an increasingly recognized disorder of excess sweating that may affect focal sites such as the axillae, the palms of the hands, the soles of the feet, or the face, or that may present more generally. Hyperhidrosis leads to substantial embarrassment and disability. Medical treatments such as systemic and topical pharmacologic agents as well as surgery, including sympathectomy, have been employed. More recently, botulinum neurotoxin (BoNT), which blocks the autonomic innervation of the sweat glands, has emerged as an effective and well-tolerated approach. Approved by the FDA for the treatment of severe primary axillary hyperhidrosis, onabotulinumtoxinA and other BoNT formulations are also being investigated in the management of palmar hypersecretion, gustatory sweating, and hypersecretory disorders such as excess drooling (sialorrhea), chronic rhinitis, and hyperlacrimation. Duration of relief of symptoms with BoNT varies with diagnosis but may last up to several months. BoNT injection is less invasive than surgery and shows promise for a range of hyperhidrosis and other secretory disorders beyond axillary hyperhidrosis.

Headache disorders are commonly encountered by physicians in the outpatient setting. Approximately 45 million Americans are affected by headache disorders, with tension-type headache being the most prevalent primary headache disorder in the population, while migraine is most prevalent in the physician’s office.1 Distinguishing primary from secondary headache is an important first step in headache diagnosis. Clinical features of the different types of headache disorders vary based on headache duration, frequency, severity, location, and other features. Treatment of headache disorders includes lifestyle and risk-factor modification and pharmacotherapy. Pharmacologic treatment for headache disorders can be either abortive or prophylactic. However, many patients are treatment-resistant or undertreated. Certain headache disorders may be successfully treated with injections of botulinum neurotoxin type A. Results from two recent clinical trials of 1384 adult patients demonstrate that the botulinum neurotoxin type A onabotulinumtoxinA (Botox) is an effective and safe prophylactic treatment for chronic migraine. OnabotulinumtoxinA is approved in the United States and the United Kingdom for the preventive treatment of headaches in adults with chronic migraine. The use of botulinum neurotoxin in the treatment of chronic headache disorders is the focus of this module.

Botulinum neurotoxin has become a powerful tool in the treatment of many clinical disorders, most of which are characterized by abnormal, excessive or inappropriate muscular activity. Since this neurotoxin inhibits cholinergic transmission at neuromuscular and autonomic postganglionic synapses, it can be used in many conditions to relax muscles or reduce glandular secretions. In these CME-certified chapters, clinicians can learn about the role that botulinum neurotoxin may have as a treatment option. The underlying scientific mechanisms by which the neurotoxin exerts its effects is also discussed in a separate chapter.

Lower urinary tract symptoms (LUTS) from genitourinary conditions such as overactive bladder, detrusor-sphincter dyssynergia, interstitial cystitis, benign prostatic hyperplasia, prostatitis are relatively common. Currently available medical and surgical management for these conditions leaves room for improvement. Beyond applications in plastic surgery, dermatology, and neurology, botulinum neurotoxin (BoNT) injection has been studied for the management of LUTS caused by these genitourinary conditions. BoNT affects hypercontractability, hypersensitivity, and glandular hypertrophy. Dose and duration vary according to the disease being treated as well as the particular BoNT product. In general, over the past 6 years, numerous urological studies have shown promising results with symptom relief of up to 6 months or longer as well as improvement in quality of life. BoNT is generally well tolerated, with some impact on postvoid residual urine and urinary tract infection. The optimal dose dilution, number, and location of injection are still under investigation. Botulinum neurotoxin shows promise for treating a variety of genitourinary conditions affecting the lower urinary tract.